1. Technical Field
The present invention is in the field of immunology, especially detection, prevention and treatment of HIV-1 infection and AIDS therapy. More particularly, it concerns monoclonal antibodies, drugs and vaccines made from these antibodies and methods based on the use of these antibodies, drugs and vaccines for analytical and/or clinical applications.
2. Description of Related Art
In the sera of human immunodeficiency virus type 1 (HIV-1) infected patients, anti-virus antibodies can be detected over a certain period after infection without any clinical manifestations of the acquired immunodeficiency syndrome (AIDS). At this state of active immune response, high numbers of antigen-specific B-cells are expected in the circulation. These B-cells are used as fusion partners for the generation of human monoclonal anti-HIV antibodies.
Monoclonal antibodies can be produced by known procedures, e.g., as described by R. Kennet et al. in "Monoclonal Antibodies and Functional Cell Lines; Progress and Applications". Plenum Press (New York), 1984.
Further materials and methods applied are based on known procedures, e.g., such as described in J. Virol. 67:6642-6647, 1993.
Monoclonal antibodies and in particular human monoclonal antibodies have been widely used in the last few years in order to improve the understanding of HIV-1 neutralization by antibodies released upon immunization with HIV-1 derived immunogens or upon infection in afflicted patients (J. Virol. 62:2107-2114, 1988; Immunology 76:515-534, 1992; J. Virol. 67:6642-6647, 1993; U.S. Pat. No. 5,087,557). Many efforts have been made to overcome the detrimental capability of the HIV-1 virus to rapidly change its morphology under immunological pressure and thereby to escape the capture by antibodies released from a patient's immune system or developed and applied by researchers. As a result thereof, there is presently no reliable antibody-based (nor any other) vaccine for active or passive immunization on the market.
One significant step forward has been made when an antigenic determinant on the smaller subunit gp41 of the HIV-1 envelope glycoprotein gp160 was found (EP 570 357 A2), which corresponds to the amino acid sequence "ELDKWA" located at amino acid position number 662 to 667 of gp41 of HIV-1 isolate BH10. The authors report therein an HIV-1 neutralizing human monoclonal antibody specifically binding to said antigenic determinant. The antibody proved to be a powerful tool for biochemical analysis of the binding epitope and its variability. The discovery of the highly conserved state of said gp41-epitope gave rise to the hope of possibly finding a vaccine composition suitable for more reliable prevention of human individuals from HIV-1 infection and/or for more successful therapeutic treatment of infected patients.
The results reported in EP 570 357 A2 motivated the present inventors to intensify their research activities which finally led them to the novel and inventive findings herein disclosed.
However, in spite of promising results of the art relating to the use of HIV-1 neutralizing monoclonal antibodies, there is at least one major drawback to this sort of approach. It lies in the wide-spread use of laboratory strains of HIV-1 isolates, which have become adapted to lab-conditions and are more or less attenuated and hence only poorly--if at all--representative of the properties and behaviour of primary HIV-1 isolates. Consequently, promising vaccine compositions drawn against laboratory HIV-1 strains frequently proved non-efficacious when applied against primary HIV-1 isolates, e.g., of blood samples of infected persons (see J. Cohen, Science 262:980-981, 1993).
The second major drawback was and still is the ability of the HIV-1 virus to escape antibody capture by morphological variation, which very often renders the remarkable efforts of the researchers almost useless. Such escape mutants may be characterized by a change of only one or several of the amino acids within one of the targeted antigenic determinants and may occur, e.g., as a result of spontaneous or induced mutation.